Synthesis and antitumor activity evaluation of some 1, 2, 4-triazine and fused triazine derivatives

Article abstract of DOI:10.1080/00397911.2018.1482350

Reactions of 3-hyrazino-5,6-diphenyl-1,2,4-triazine with various carbonyl compounds such as ethyl acetoacetate, acetylacetone, benzoin, isatin, phthalic anhydride, phenyl isocyanate and acetic anhydride were discussed. Its reactions with α, β unsaturated

Full text of DOI:10.1080/00397911.2018.1482350

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis and antitumor activity evaluation of
some 1, 2, 4-triazine and fused triazine derivatives
Mohsen K. Abou-Elregal, Amira T. A. Mohamed, Ahmed S. A. Youssef, Magdy
M. Hemdan, Sandy S. Samir & Wael S. I. Abou-Elmagd
To cite this article: Mohsen K. Abou-Elregal, Amira T. A. Mohamed, Ahmed S. A. Youssef, Magdy
M. Hemdan, Sandy S. Samir & Wael S. I. Abou-Elmagd (2018) Synthesis and antitumor activity
evaluation of some 1, 2, 4-triazine and fused triazine derivatives, Synthetic Communications, 48:18,
2347-2357, DOI: 10.1080/00397911.2018.1482350
To link to this article: https://doi.org/10.1080/00397911.2018.1482350
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2018, VOL. 48, NO. 18, 2347–2357
https://doi.org/10.1080/00397911.2018.1482350
Synthesis and antitumor activity evaluation of some
1, 2, 4-triazine and fused triazine derivatives
Mohsen K. Abou-Elregal, Amira T. A. Mohamed, Ahmed S. A. Youssef,
Magdy M. Hemdan, Sandy S. Samir and Wael S. I. Abou-Elmagd
Chemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt Abassia
ABSTRACT
ARTICLE HISTORY
Received 12 March 2018
Reactions of 3-hyrazino-5,6-diphenyl-1,2,4-triazine with various car-
bonyl compounds such as ethyl acetoacetate, acetylacetone, benzoin,
isatin, phthalic anhydride, phenyl isocyanate and acetic anhydride
were discussed. Its reactions with a, b unsaturated compounds such
as arylidinemalononitrile, diethyl acetylenedicarboxylate, dibenzyli-
dine hydrazine were studied. These reactions led to the formation of
various triazine and fused-triazine derivatives. The antitumor activity
of the synthesized compounds was tested against HePG2 and
MCF-7 cell lines. Some of the tested compounds were most active,
whereas other compounds exhibited little or no activity.
KEYWORDS
1; 2; 4-Triazine;
triazolotriazine; triazinotria-
zepine; triazinotriazine
GRAPHICAL ABSTRACT
Introduction
1,2,4-Triazines and their fused derivatives play an important role in medicinal chemistry
due to their high biological activity. They are known to possess a broad spectrum of
pharmacological activities such as antiviral,[1] antibacterial, fungicidal, insecticidal, herbi-
cides, hypotensive, hypothermic activities,[2–5] in vitro supporting their anti-HIV and
anticancer activities,[6–12] biological inhibitors[13–17], anti-epileptic drug.[18] Condensed
CONTACT Sandy S. Samir
sandysamy@sci.asu.edu.eg
Chemistry Department, Faculty of Science, Ain Shams
University, Cairo, Egypt Abassia.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed here.
ß 2018 Taylor & Francis

2348
M. K. ABOU-ELREGAL ET AL.
1,2,4-triazines found various applications as pharmaceuticals, herbicides, pesticides,
and dyes,[19] growth inhibitory activity against leukemic cell lines and wide range of
cancer cells,[20–22] antitumor and antifungal,[23,24] antiviral,[25–30] antimicrobial,[31–33]
anti-HIV,[34] antimycobacterial,[35] anxiolytic,[36] and antidepressant agent.[37] These
diverse biological activities initiated our interest to synthesize some 1,2,4-triazine and
N-bridgehead fused derivatives of anticipated antitumor activities.
Results and discussion
3-hydrazino-5,6-diphenyl-1,2,4-triazine was synthesized according to the reported proce-
dure[38]and exists as an equilibrium mixture of the two tautomeric forms 1a, b
(Equation 1)
Reaction of 1 with carbondisulfide in ethanol in the presence of a base like KOH,
afforded the cycloaddition product triazolotriazine 2. Its structure is evidenced from
microanalytical as well as spectral data. IR spectrum shows two characteristic absorption
bands at 3196 and 3114 cmꢀ1corresponding to (NH) and 1178 cmꢀ1corresponding to
(C¼S) groups. Further support for the assigned structure is gained by studying its
1HNMR spectrum that shows one broad singlet signal for (NH) at d (ppm) 13.52 in add-
ition to multiplet signals for the aromatic protons. The EIMS spectrum of compound 2
does not show the molecular ion peak, but it shows (Mꢁþ-1) peak in addition to some of
abundant peaks. When thione derivative 2 is treated with hydrazine hydrate in boiling
dioxane, it gave the dimeric form of hyrazone derivative 3 with a removal of H2S gas. The
1
structure of compound 3 is substantiated from its infrared and HNMR spectra (cf.
Supplementary experimental). Heating of 3-hydrazino derivative 1 with phenyl isocyanate
in dry benzene gave the corresponding addition product semicarbazide 4. The structure
of compound 4 is deduced from its microanalytical and spectral data. The IR spectrum
exhibits absorption bands for NH and C¼O groups. Further proof is gained from its
1HNMR spectrum which exhibits three exchangeable broad singlet signals for protons of
three NH groups. The down field value for the signal of one of the three protons is in
accordance with the existence of compound 4 as the chelated form shown in (Scheme 1).
Treatment of compound 4 with acetic anhydride yielded the triacetyl derivative 6 instead
1
of the triazolotriazine derivative 5. Inspection of the HNMR spectrum of compound 6
revealed the appearance of two singlet signals in the up-field region for three methyl
groups. The integration value for the signal atd 2.38 ppm is equivalent to the multiple
value of the signal at d 2.73 ppm. This suggests that the first signal corresponds to protons
of two magnetically equivalent methyl groups. Furthermore, the spectrum is devoid of
any signals for NH protons. A chemical proof for the suggested structure is gained by pre-
paring an authentic sample, through reacting of compound 1 with acetic anhydride. It
was identical in all respects m.p, m.m.p and TLC with compound 6. Further support is

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gained from its mass spectrum that revealed the correct molecular ion peak beside some
of abundant peaks. All previous reactions are presented in (Scheme 1).
The conversion of compound 4 into 6 is depicted in (Scheme 2)
The treatment of compound 1 with dibenzylidene hydrazine 7 and/or pyrazolidine
derivative of malononitrile 8 in boiling ethanol, furnished the benzalhydrazone and pyr-
1
azolidinehydrazone derivatives 9 and 10, respectively (Scheme 3). The HNMR spec-
trum of 9 shows two singlet signals at d 8.276, 11.933 ppm correspond to protons of
Scheme 1. Reactions of 1 with carbon disulfide, phenylisocyante and acetic anhydride.
Scheme 2. Mechanistic pathway for the conversion of compound 4 into 6.

2350
M. K. ABOU-ELREGAL ET AL.
Scheme 3. Reactions of 1 with dibenzylidene hydrazine 7 and/or pyrazolidine derivative of
malononitrile.
1
imino methine (CH¼N) and (NH) groups. However, the HNMR spectrum of 10 shows
three singlet signals at d 8.44 ppm (CH¼N), 8.943 ppm(CH) of pyrazole and 11.787 ppm
(NH). Further evidence for the structures of compounds 9 and 10 is gained from their
mass spectra that revealed their molecular ion peaks as well as some of important peaks.
The structures of both compounds 9 and 10 were confirmed chemically by preparing
authentic samples from reactions of 1 with benzaldehyde and/or 1,3-diphenyl pyrazol-4-
carbaldehyde. They were identical in all respects m.p, m.m.p and tlc.
The suggested mechanistic pathways for the formation of hydrazones 9 and 10 are
presented in (Scheme 4 and 5).
Heating of compound 1 with phthalic anhydride in acetic acid under reflux condition
gives the isoindoline 11 via nucleophilic addition followed by cyclization. The IR spec-
trum of 11 revealed the presence of one absorption band at 3190 cmꢀ1 (NH) and two
absorption bands at1791 and 1743 cmꢀ1 attributable to the vibrational coupling of two
1
carbonyl groups. The HNMR spectrum is in accordance with the proposed structure
(cf. Supplementary experimental). Reaction of the hydrazino derivative 1 with isatin in
DMF as a solvent yielded the Schiff’s base derivative 12. The structure of 12 is estab-
1
lished by studying its IR as well as HNMR spectra. The IR spectrum shows absorption
1
bands characteristic for NH and C¼O groups. The HNMR spectrum shed further light
on the proposed structure as it shows two broad singlet signals in the down field region
for protons of 2 NH groups in addition to multiple signals for the aromatic protons.
The down field value for the signal of NHa proton as well as the lower absorption fre-
quency of C¼O group is a good evidence for existence of compound 12 as the chelated
form shown in (Scheme 6). The mass spectrum of compound 12 does not show the
molecular ion peak, probably due to its ready decomposition in the ionization chamber,
but it shows some abundant peaks.
Treatment of 3-hydrazinoderivative 1 with ethyl acetoacetate in boiling ethanol
afforded the corresponding condensation product 13. The IR spectrum of 13 revealed

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Scheme 4. Mechanistic pathway for the formation of hydrazone 9.
Scheme 5. Mechanistic pathways for the formation of hydrazones 9 and 10.
the presence of absorption bands at 3281 cmꢀ1 attributable to (NH) and the carbonyl of
1
ester group at 1733 cmꢀ1. Inspection of the HNMR spectrum of compound 13 revealed
the existence of signals corresponding to protons of NH, CH2 and CH3CH2 groups as
well as aromatic protons. The appearance of two singlet signals for the methylene pro-
tons of N¼C–CH2C¼O group with integration ratio 1:3 suggests the existence of com-
pound 13 as a mixture of two diasteriomeric forms syn and anti. The lower d value for
the signal of methylene protons of anti-isomer as compared with those of syn isomer is
due to the extension of conjugation in the Ar–N¼C– moiety that leads to increase the
electron density at the carbon bearing the methylene group.
On the other hand, cyclocondensation is produced by reacting of 3-hyrazino deriva-
tive 1 with acetylacetone in boiling ethanol to give triazinotriazepine derivative 14.
1
The IR spectrum shows no absorption bands for (NH) and (C¼O) groups. The HNMR
spectrum is in accordance with the proposed structure (cf. Supplementary experimental).

2352
M. K. ABOU-ELREGAL ET AL.
Scheme 6. Reactions of 1 with phthalic anhydride and isatin.
Scheme 7. Reactions of
1 with Ethyl acetoacetate, acetyl acetone, benzoin and diethyl
acetylenedicarboxylate.
Similarly, the cyclocondensation product triazinotriazine derivative 15 was achieved by
1
reaction of 3-hyrazino derivative 1 with benzoin. The HNMR spectrum of compound
15 revealed the appearance of two singlet signals, one in the up-field region for the ben-
zylidene proton (CH) and the other in the down field region for NH proton. This sug-
gests the existence of compound 15 as an equilibrium mixture of toutomers 15a and 15b
in the ratio of 3:2 (Scheme 7). Compound 1 undergoes Michael addition to diethyl ace-
tylenedicarboxylate to afford the addition product 16. The structure of 16 is established

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Table 1. Cytotoxic activity of some compounds against
human tumor cells.
In vitro cytotoxicity IC50 (mM)ꢁ
No.
Compounds
HePG2
4.50 0.2
MCF-7
4.17 0.2
DOX
1
2
2
4
31.75 2.5
7.21 0.8
35.38 2.4
9.72 0.9
3
4
5
6
7
8
9
10
11
12
14
16
12
13
11
10
3
9
15
6
72.13 3.9
39.49 2.6
61.84 3.5
27.93 2.1
19.18 1.7
82.34 4.6
55.35 3.2
76.58 4.1
48.16 2.9
9.11 1.0
68.23 3.8
45.08 2.8
67.14 3.7
26.99 2.0
21.10 1.8
72.15 4.1
49.27 3.0
91.48 5.2
58.36 3.4
12.84 1.1
ꢁIC50 (mM): 1–10 (very strong). 11–20 (strong). 21–50 (moder-
ate). 51–100 (weak) and above 100 (noncytotoxic).
by studying its IR spectrum that shows absorption bands corresponding to NH and
C¼O groups. Further evidence for the suggested structure of compound 16 is gained
1
from its HNMR spectrum that exhibits signals for NH, alkyl and aromatic protons. The
down field value for the signal of NH proton, as well as the lower absorption frequency
of one of the two carbonyl ester groups is in a good agreement with the existence of
compound 16 as the chelated form shown in (Scheme 7).
Evaluation of the antitumor activity
The anti-tumor efficacy of the compounds against HePG2 and MCF-7 cell lines was
demonstrated compared with doxorubicin. The obtained results revealed that com-
pounds 4, 11 and 6 were the most active derivatives among the series of tested com-
pounds, whereas other compounds exhibited little or no activity. The effective dose
calculated as IC50, which correspond to the compound concentration resulted in 50%
mortality in the total cells count and presented in (Table 1, Fig 1).
Experimental
Melting points were determined using an electrothermal Gallenkamp Scientific melting
point apparatus and are uncorrected. The infrared (IR) spectra were recorded on
Nicolet 7600 (USA)FT-IR infrared spectrophotometer using the KBr pellet technique at
1
the central laboratory of faculty of science, Ain shams university. HNMR spectra were
recorded on a GEMINI 300 BB-400 MHz spectrometer using tetramethylsilane (TMS) as
internal standard in dimethyl sulfoxide (DMSO-d6) as a solvent with chemical shift d
expressed in ppm and 13C-NMR spectra were recorded on the same spectrometer at
75 MHz and referenced to solvent signal d ¼ 39.50 ppm for DMSO-d6 at the main
defence chemical laboratory. Mass spectra were measured on a GC-MSQP 1000-Ex spec-
trometer at the regional center for Mycology and Biotecnology of Al-Azhar university
and on Agilent technologies 5977 AMSD 7890B CTC system at the central laboratory of

2354
M. K. ABOU-ELREGAL ET AL.
100
In vitro Cytotoxicity
90
80
70
60
HePG2
MCF-7
IC50 (µM) 50
40
30
20
10
0
2
4
14 16 12 13 11 10
3
9
15
6
Compound NO.
Figure 1. Cytotoxic activity of some compounds against human tumor cells. IR spectrum
of compound 2.
faculty of science, Ain shams university. Elemental analyses were carried out at the
microanalytical center of faculty of science, Cairo University. Follow-up of the
reactions and checking the homogeneity of the compounds were made by TLC on silica
gel-protected aluminum sheets (F254, Merck) and the spots were detected by exposure
to UV-lamp. The anticancer activity was done at Micro Analytical Center at
Mansoura University.
General procedure for the reaction of the hydrazino 1 with carbon disulfide
A solution of compound 1 (0.5g, 0.002 mol) in (10 mL) ethanolic potassium hydroxide
10% and carbon disulfide (0.144g, 0.002 mol) was refluxed for 7h. Cooled then neutral-
ized with ice-cold hydrochloric acid. The solid obtained was collected by filtration and
recrystallized from a mixture of petroleum 60–80 ꢂC and benzene (1:1).
6,7-Diphenyl-[1,2,4] triazolo[4,3-b][1,2,4]triazine-3(2H)-thione2
Orange crystals (50%), mp 208-210 ꢂC, (petroleum 60–80 ꢂC and benzene (1:1)); FTIR
(KBr) cmꢀ1: 3196, 3114 (NH), 3089, 3054 (Aryl-H), 1664 (C¼N), 1178 (C¼S).1 HNMR
(DMSO-d6): d 7.22–7.45 (m, 10H, Ar–H), 13.52 (br.s, 1H, NH, exchangeable). MS
(70 ev) m/z (%): 305.074 (Mꢁ, missed), 220(36), 192(87), 191(19), 190(20), 178(41),
165(100), 103(19), 104(19), 61(35). Anal. calcd for C16H11N5S (305.359): C, 62.93; H,
3.63; N, 22.93; S, 10.50. Found: C, 62.78; H, 3.64; N, 22.88; S, 10.52.
General procedure for the reaction of the semicarbazide 4 with acetic anhydride
Method A: A solution of compound 4 (1g, 0.0026 mol) in acetic anhydride (20 mL) was
boiled under reflux for 2h. The resulting solid was poured onto crushed ice and the
product that separated was filtered off, washed with water and then recrystallized from
petroleum 60–80 ꢂC.

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Method B: A solution of compound 1 (0.5 g, 0.002 mol) in acetic anhydride (15 mL)
was refluxed for 1 h. The reaction mixture was then poured onto crushed ice and the
solid product that separated was filtered off, washed with water and then recrystallized
from petroleum 60–80 ꢂC.
N, N'-diacetyl-N'-(5, 6-diphenyl-1, 2, 4-triazin-3-yl)-acetohydrazide 6
Pale yellow crystals (84%), mp138–140 ꢂC (lit.40 m.p. 143–144 ꢂC), (petroleum
60–80 ꢂC); FTIR (KBr) cmꢀ1: 3065, 3011 (Aryl-H), 2937 (Alkyl-H), 1731, 1705 (C¼O),
1
1599 (C¼N), 1580 (C¼C). HNMR (DMSO-d6): d, 2.38 (s, 6H, 2CH3), 2.73 (s, 3H,
CH3), 7.37–7.51 (m, 10H, Ar-H) MS(70 ev) m/z (%): 389.149 (Mꢁþ,19), 305(43),
288(27), 276(13), 263(39), 207(16), 179(16), 178(100), 176(15), 165(13), 104(12).
Anal.calcd for C21H19N5O3 (389.415): C, 64.77; H, 4.92; N, 17.98; Found: C, 64.64; H,
4.93; N, 18.04.
Antitumor bioassay
Materials and methods
Cell line
Hepatocellular carcinoma HePG-2 and mammary gland MCF-7. The cell line was
obtained from ATCC via Holding company for biological products and vaccines
(VACSERA), Cairo, Egypt.
Chemical reagents
The reagents RPMI-1640 medium,MTT and DMSO (sigma co., St. Louis, USA), Fetal
Bovine serum (GIBCO, UK) .Doxorubicin was used as a standard anticancer drug
for comparison.
MTT assay
The different cell line mentioned above were used to determine the inhibitory effects of
compounds on cell growth using the MTT assay[41,42]. This colorimetric assay is based
on the conversion of the yellow tetrazolium bromide (MTT) to a purple formazan
derivative by mitochondrial succinate dehydrogenase in viable cells. The cells were cul-
tured in RPMI-1640 medium with 10% fetal bovine serum. Antibiotics added were 100
units/ml penicillin and 100 mg/ml streptomycin at 37 C in a 5% Co2 incubator. The cells
were seedes in a 96-well plate at a density of 1.0 ꢃ 104 cells/well. at 37 ꢂC for 48 h under
5% CO2. After incubation, the cells were treated with different concentration of com-
pounds and incubated for 24 h. After 24 h of drug treatment, 20 ml of MTT solution at
5 mg/ml was added and incubated for 4 h. Dimethyl sulfoxide (DMSO) in volume of
100 ml is added into each to dissolve the purple formazan formed. The colorimetric assay
is measured and recorded at absorbance of 570 nm using a plate reader (EXL 800). The
relative cell viability in percentage was calculated as (A570 of untreated sample/A570 of
untreated sample)ꢃ100.

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M. K. ABOU-ELREGAL ET AL.
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